DE19924688A1 - New salicylic alcohol derivatives - Google Patents

Abstract

The present invention relates to novel salicyl alcohol derivatives which are provided with valuable biological activities. The invention also relates to a method for producing the same and the utilisation in cosmetics and pharmacy.

Description

The present invention relates to new salicyl alcohol derivatives, processes for their Production and cosmetic and / or containing these compounds pharmaceutical preparations.

Many naturally occurring alkyl and phenol glucosides show antiviral, antimicrobial and partially anti-inflammatory effects (S. Matsamura, K. Imai, K. Kawada and T. Uchibori, Surface activities, biodegradability, and antimicrobial properties of n-alkyl-glucosides, mannosides and galactosides, J. At the. Oil Chem. Soc. 67: 996-1001 (1990); T. Hedner and B. Everts, The early clinical history of salicylates in rheumatology and pain, Glin. Rheumatol. 12, 17-25 (1998)). Especially the watery extracts of willow bark (Salix alba, pupurea or fragilis) and the poplar are known for their anti-inflammatory effects. Therefore, appropriate extracts are used in medicinal teas, but also in Cosmetic products, e.g. B. used to reduce skin irritation, as in the application DE 196 15 577. As important ingredients of the bark of willows apply salicin and salicylic acid (o-hydroxybenzoic acid), des others are salicortin (2 - [[[(1-hydroxy-6-oxo-2-cyclohexen-1- yl) carbonyl] oxy] methyl] phenyl-β-D-glucopyranoside), fragilin (acetyl-salicin) and in Poplar bark still contains populin (benzoyl salicin). Mainly salicylic acid and its derivatives like acetylsalicylic acid have been examined very closely for anti-inflammatory effects: as non-steroidal anti-inflammatory agents (English non-steroidal anti-inflammatory drugs, NSAID) they inhibit prostaglandin synthesis (J.R. Vane, Inhibition of prostaglandin synthesis as a mechanism of action of the aspirin-like drugs, nature, 231, 232-235 (1971)).  

Prostaglandins are used in response to various exogenous, cell-specific stimuli through the enzymes prostaglandin synthase-1 and -2 (PGHS-1 and -2) catalyzed dioxygenation of polyunsaturated fatty acids, in particular Arachidonic acid. As autocrine and paracrine tissue hormones it amplifies injuries, skin irritation, wound healing processes and inflammatory reactions formed.

Normal epidermis already contains significant amounts of prostaglandins, which are obviously produced by PGHS-1 because PGHS-2 is not expressed. In irritated skin, prostaglandins (especially PGE ₂ and PGF _2? From the keratinocytes), as local inflammation mediators, cause both dilation (dilation) and increased permeability of blood vessels and are therefore responsible for the development of redness, warming and swelling, which are typical of inflammatory reactions Haut (G. Fürstenberger, Role of eicosanoids in mammalian skin epidermis. Cell. Biol. Rev. 24, 1-90 (1990); G. Fürstenberger, V. Kinzel, M. Schwarz and F. Marks, Partial inversion of the initiation -promotion sequence of multistage tumorigenesis in the skin NMRI mice; Science 230, 76-78 (1985)), but also involved in the development of regenerative epidermal hyperplasia. Inhibitors of prostaglandin synthesis can prevent these undesirable effects.

In addition to the salicin found in willows and poplars mentioned at the beginning Derivatives from the literature are the extraction of benzoyl salicin from plants (L. by Hoofet al., Plant viral agents, Vl. Isolation of antiviral phenolic glucosides from Populus cultivar Beaupre by droplet counter-current chromatography, J. Nat. Prod. 52, 875-878 (1989)) and the enzymatic preparation of phenylbutyryl salicin known (R. T. Otto, U. T. Bornscheuer, C. Syldatk and R. D. Schmid, Lipase catalyzed synthesis of arylaliphatic esters of D (+) - glucose, alkyl- and aryl glucosides and characterization of their surfactant properties, J. Biotechnol. 64, 231-237 (1998)).

Although numerous pharmacologically active substances already exist in the literature that intervene, for example, in the inflammatory cascade, there is still a need for more effective, poor side effects Active substances. There is also a need for active ingredients with a good one  Absorbability and rapid penetration into the skin, which is also good in pharmaceutical or cosmetic formulations must be incorporated.

Surprisingly, it has now been found that certain salicyl alcohol derivatives, the compounds related to their chemical structure as salicin can be conceived for use in cosmetics and pharmacy useful pharmacological effects such as B. anti-inflammatory, show antipyretic, anti-inflammatory and / or analgesic effects and the Disadvantages of the prior art described above not or only in show less.

The invention relates to salicyl alcohol derivatives of the general formula (I)

R ¹ -OCH ₂ -Ph-OZ- (R ² ) _n (I),

Process for their preparation and cosmetic containing them or pharmaceutical preparations.

The compounds have valuable pharmacological properties, such as. B. an inhibitory effect on prostaglandin synthesis.

Stand in the general formula (I)
R ^{1 represents} a hydrogen atom or a radical C (O) R ³ ,
wherein R ^{3 is} an alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, or aryl radical having 1 to 26 carbon atoms and / or 1-10 heteroatoms, which is unbranched or branched, mono- or polyunsaturated and / or substituents on the carbon skeleton and / or can carry the heteroatoms means
Ph for the 1,2-phenylene radical,
Z for a sugar which is semi-acetally bound to the aromatic radical Ph in (I) and which is substituted n-times with R ^{2 in an} ester-like manner, where the sugar can be a mono-, di-, oligo- or polysaccharide,
n is an integer between 0 and m, where m is the number of free hydroxyl groups present in the semiacetal bond to the aromatic radical Z,
R ^{2 represents} a hydrogen atom or a group C (O) R ⁴ , where R ^{4 is selected} from the same group as R ³ , and where R ¹ and R ^{2 may be the} same or different, with the proviso that at most one of the two radicals R ¹ or R ^{2 is} hydrogen when Z = glucose,
and with the limitations
that when Z is glucose and R ^{2 are} hydrogen, the radical R ^{1 can} not be acetyl, benzoyl or (1-hydroxy-6-oxo-2-cyciohexen-1-y1) carbonyl,
and in the event that R ^{1 is} hydrogen, Z is glucose and n = 1 and the glucose radical on its primary hydroxyl group is substituted by R ² , the radical R ² cannot be 4-phenyl-butyryl.

Preferably, for the case that R ¹ is hydrogen, Z is glucose and n = 1 and the glucose residue is substituted at its primary hydroxyl group with R ^2, the radical R ² corresponding carboxylic acid R ⁴ COOH no hydrophobic aromatic carboxylic acid.

For the meanings mentioned in the definition of the radicals come, for example, for R ³ and R ^{4 are} hydrogen, the methyl, ethyl, propyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl -, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, heneicosyl, vinyl, 1-propenyl, 2-propenyl, 2- Butenyl, 8-pentadecenyl, 8-heptadecenyl, Z, Z-8.11 heptadecadienyl, Z, Z, Z-8,11,14-heptadecatrienyl, 4,7,10,13,16-nonadecapentaenyl -, 3,6,9,12,15,18-heneicosahexaenyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, o-, m- or p-hydroxy-phenyl-, o-, m- or p-Hydroxy-phenyimethyl-, o-, m- or p-hydroxy-phenylethyl-, o-, m- or p-hydroxy-phenylpropyl-, o-, m- or p-hydroxy-phenylbutyl-, 3,4, 5- trihydroxyphenyl, 3-phenylvinyl, o-, m- or p-hydroxy-3-phenylvinyl, 3- (3,4-dihydroxyphenyl) vinyl or 3-pyridyl group, with additional substituents such as. B. a halogen atom, an alkyl, hydroxy, alkoxy, phenyl, nitro, amino, acetylamino or carboxy group, and phenolic hydroxyl groups as phenolate salts with alkali or alkaline earth metals may be present in Consideration.

The invention thus furthermore relates to salicyl alcohol derivatives of the general formula (I) in which at least one of the two radicals R ¹ and R ^{2 is} a hydrogen atom, the benzoyl, phenylacetyl, phenylpropionyl, phenylbutyryl, phenylvaleroyl, o, m- or p-hydroxy-benzoyl-, o-, m- or p-hydroxy-phenylacetyl-, o-, m- or p-hydroxy-phenylpropionyl-, o-, m- or p-hydroxy-phenylbutyryl-, o -, m- or p-Hydroxy-phenylvaleroyl-, 3,4,5-trihydroxybenzoyl-, 3-phenylacryloyl-, o-, m- or p-hydroxy-3-phenylacryloyl- or 3- (3,4-dihydroxyphenyl) -acryloyl group means.

Preferred salicyl alcohol derivatives of the general formula (I) are those in which n = 1 and R ^{1 is} hydrogen.

For the radical Z in the general formula (I) there are, for example, threose, Erythrose, arabinose, lyxose, ribose, xylose, allose, old rose, galactose, Glucose, Gulose, Idose, Mannose, Talose, Fructose, being the most natural occurring stereoisomers of sugar are preferred, as well as those of them composite di-, oligo- and polysaccharides.

Preferred salicyl alcohol derivatives of the general formula (I) are those in where Z is D-glucose.

To prepare the compounds according to the invention, for example basically all processes described in the literature for the production of Carboxylic acid esters are used (cf. C. Ferri, reactions of organic Synthesis, Thieme-Verlag, Stuttgart 1978), but preferably esterifications, Transesterification and acylation with activated carboxylic acid derivatives.

Another object of the invention is therefore a method for manufacturing the compounds according to the invention (I), which is characterized in that  an alcoholic component with a carboxylic acid, a carboxylic acid ester or an activated carboxylic acid derivative in the presence of suitable catalysts is esterified or transesterified.

An activated carboxylic acid derivative is, for example, a To understand carboxylic acid chloride or carboxylic anhydride, which under Schotten-Baumann conditions with an alcohol component to an ester can be implemented.

The compounds according to the invention can be prepared, for example, by esterification of an alcohol of the structure

HIGH ₂ -Ph-OZ (II)

with a carboxylic acid R ³ COOH and / or R ⁴ COOH, in the case of esterification with both carboxylic acids the esterification can take place in one step or in two successive steps,
and wherein Ph, Z, R ³ and R ^{4 have} the meanings as described above for formula (I).

The compounds according to the invention can also be prepared by transesterification of an alcohol of structure (II) with carboxylic acid esters R ³ COOR ⁵ and / or R ⁴ COOR ⁵ , where R ^{5 is} an alkyl group having 1 to 4 carbon atoms and, in the case of transesterification, with both Carboxylic acid esters the transesterification can take place in one step or in two successive steps,
and wherein Ph, Z, R ³ and R ^{4 have} the meanings as described above for formula (I).

In the preparation of the compounds of the invention according to the usual Methods of chemical synthesis come about because of the presence of several Free hydroxyl groups in the alcoholic component (II) or a partial ester of these usually to form mixtures of simple  and multiply substituted products, so that the introduction and removal of Protecting groups is necessary when targeting a particular connection wants to synthesize.

By using activated carboxylic acid derivatives, by-products and often also undesirable by-products, which make processing more difficult, reduce the yields of the desired product and pollute the environment. These disadvantages can be avoided or at least reduced by the Preparation of the compounds according to the invention by enzymatic means (e.g. based on that described in German application DE 197 53 789.8 Method) or by biotransformation with plant cell cultures (M. Ushiyama, S. Kumagai and T. Furuya, Phytochemistry 28, 3335 (1989)).

The invention accordingly furthermore relates to a method for the production of the compounds (I) according to the invention, which is characterized in that an alcoholic component with a carboxylic acid or a Carboxylic acid esters esterified with one or more enzymes as catalysts or is transesterified.

Suitable enzymatic processes for esterification or transesterification are described for example in K. Drauz and H. Waldmann, Enzyme Catalysis in Organic Synthesis, VCH-Verlag, Weinheim 1975.

The salicyl alcohol derivatives according to the invention have valuable biological Activities on such. B. anti-inflammatory, anti-pyretic, anti-inflammatory or analgesic effects. For example, known compounds such as salicin with the invention Compounds achieve a greater inhibition of prostaglandin synthesis, what with is linked to the higher lipophilicity of these compounds. Prerequisite for the better effect is u. a. efficient absorption by the cell membranes of the keratinocytes. The lipid solubility is more glycosidic Connections result from the ratio of hydrophilic and hydrophobic Proportion that is described by the HLB value. Salicin has an HLB value  of about 12 rather than a water-soluble, salicine ester with values of partial on the other hand, well below 10 should be classified as fat-soluble molecules. This makes the transport across the cell membranes clear compared to salicin improved, and compared to conventional active ingredients, which are usually only at Subcutaneous application has a sufficient effect, a cutaneous Application facilitated or made possible.

The carboxylic acid part of the salicyl alcohol derivatives according to the invention can be formed by a carboxylic acid R ³ COOH and / or R ⁴ COOH, which itself has an intrinsic biological activity, such as. B. the sorbic acid known as fungistatic. In this way, salicyl alcohol derivatives are available which, in addition to an anti-inflammatory, antipyretic, anti-inflammatory and analgesic effect, also have other biological effects, such as. B. antioxidative, skin lightening, antibacterial, antiviral or fungistatic effects.

In addition, the compounds of the invention are particularly good at lipophilic base formulations can be incorporated and can be easily used as formulate stable emulsions.

According to the invention, the compounds of general formula (I) Manufacture of cosmetic and / or pharmaceutical preparations used.

Another object of the invention is therefore cosmetic and / or pharmaceutical preparations containing the inventive Salicyl alcohol derivatives (I).

Those obtainable using the compounds (I) according to the invention cosmetic preparations, such as hair shampoos, hair lotions, Bubble baths, shower baths, creams, gels, lotions, alcoholic and aqueous / alcoholic solutions, emulsions, wax / fat masses, stick preparations, Powders or ointments can also be used as mild auxiliaries and additives  Surfactants, oil bodies, emulsifiers, superfatting agents, pearlescent waxes, Consistency agents, thickeners, polymers, silicone compounds, fats, Waxes, stabilizers, biogenic agents, deodorant agents, antidandruff agents, Film formers, swelling agents, UV light protection factors, antioxidants, hydrotropes, Preservatives, insect repellents, self-tanners, solubilizers, Perfume oils, dyes, germ inhibitors and the like contain.

The amount of the compounds according to the invention used in cosmetic Preparations are usually in the range from 0.01 to 5% by weight, however, preferably from 0.1 to 1% by weight, based on the preparations.

Leave for the manufacture of pharmaceutical or cosmetic preparations the compounds of the general formula (I) according to the invention, if necessary in combination with other active substances, together with one or more inert customary carriers and / or Diluents, e.g. B. with cornstarch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, Tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, Water / polyethylene glycol, propylene glycol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in usual pharmaceutical preparations such as tablets, coated tablets, capsules, powders, Work in suspensions, drops, ampoules, juices or suppositories.

The to achieve a corresponding effect in pharmaceutical Applications daily dosage is expediently 0.1 up to 10 mg / kg body weight, preferably 0.5 to 2 mg / kg body weight.  

Examples example 1 6-O-phenylpropionyl- [2- (hydroxymethyl) phenyl] -β-D-glucopyranoside

5 mmol D - (-) - salicin [2- (hydroxymethyl) phenyl-β-D-glucopyranoside], 7.5 mmol phenylpropionic acid, 4 g molecular sieve, 4 ml t-butanol and 2.5 g immobilized lipase B from Candida antarctica were added for 34 hours Incubated at 60 ° C in a rotating 50 ml round bottom flask. The reaction was carried out by means of thin layer chromatography (silica gel 60 plates with fluorescent indicator; eluent: chloroform / methanol / water 65/15/2 v / v / v; visualization: UV detection and by means of acetic acid / sulfuric acid / anisaldehyde (100: 2: 1 v / v / v) - immersion reagent) detected. The product was extracted with 20 ml of dichloromethane and purified by column chromatography (silica gel F60; eluent: ethyl acetate / methanol 10/1 v / v). After cleaning, the yield was 32% (white solid).
¹³ C-NMR (CD ₃ OD): δ (ppm) = 30.9 (C-2), 38.7 (C-3), 61.6 (C-7 *), 65.2 (C-6 '), 72.2 (C-4 '), 75.6 (C-2'), 76.1 (C-5 '), 78.4 (C-3'), 103.7 (C-19, 117.6 (C-6 *), 124.5 (C-4. *), 127.6 (C-7), 130.1-131.0 (C-3 *, C-5 *, C-5, C-6, C-8, C-9), 132.8 (C-2 *), 143.4 (C- 4), 157.5 (C-1 *), 175.2 (C '= O).

Example 2 6-O-p-OH-phenylacetyl - ([2- (hydroxymethyl) phenyl] -β-D-glucopyranoside

5 mmol D (-) - salicin [2- (hydroxymethyl) phenyl-δ-D-glucopyranoside], 7.5 mmol p-OH-phenylacetic acid, 4 g molecular sieve, 4 ml t-butanol and 2.5 g immobilized lipase B from Candida antarctica were Incubated for 34 hours at 60 ° C in a rotating 50 ml round bottom flask. The reaction was carried out by means of thin layer chromatography (silica gel 60 plates with fluorescent indicator; eluent: chloroform / methanol / water 65/15/2 v / v / v; visualization: UV detection and by means of acetic acid / sulfuric acid / anisaldehyde (100: 2: 1 v / v / v) - immersion reagent) detected. The product was extracted with 20 ml of dichloromethane and purified by column chromatography (silica gel F60; eluent: ethyl acetate / methanol 10/1 v / v). After cleaning, the yield was 17% (white solid).
¹³ C-NMR (CD ₃ OD): δ (ppm) = 41.8 (C-2), 61.0 (C-7 *), 65.0 (C-6 '), 71.5 (C-4'), 74.9 (C- 2 '), 75.4 (C-5'), 77.8 (C-3 '), 103.2 (C-1'), 117.1 (C-6 *), 123.9 (C-4 *), 129.4- 132.3 (C- 2 *, C-3 *, C-5 *; C-4, C-5, C-7, C-8), 136.1 (C-3), 156.0-159.2 (C-1 *, C-6) , 173.31 (C = O).

The following were obtained in an analogous manner to that in Example 1:

Example 3 p-Chloro-phenylacetoyl - ([2- (hydroxymethyl) phenyl] -β-D-glucopyranoside ¹³

C-NMR (CD ₃

OD): δ (ppm) = 41.2 (C-2), 61.0 (C-7 *), 65.1 (C-6 '), 71.4 (C-4'), 74.9 (C-2 '), 75.2 (C-5'), 77.8 (C-3 '), 103.1 (C-1'), 117.7 (C-6 *), 123.9 (C-4 *), 129.5- 132.0 (C-3-C-5, C-7, C-8, C-2 *, C-3 *, C-5 *), 134.2 (C-6), 156.2 (C-1 *), 173.0 (C '= O).

Example 4 6-O-cinnamoyl - ([2- (hydroxymethyl) phenyl] -β-D-glucopyranoside ¹³

C-NMR (CD ₃

OD): δ (ppm) = 61.0 (C-7 *), 64.9 (C-6 '), 71.8 (04), 74.9 (C-2'), 75.4 (C-5 '), 77.9 (C-3'), 103.7 (C-1 '), 117.1 (C-6 *), 118.6 (C-2), 123.8 (C-4 *), 129.1- 131.6 (C-5 to C-9, C-2 *, C-3 *, C-5 *), 135.6 (C-4), 146.5 (C-3), 156.2 (C-1 *), 168.3 (C '= O).

Example 5 6-O-oleoyl - ([2- (hydroxymethyl) phenyl] -β-D-glucopyranoside ¹³

C-NMR (CD ₃

OD): δ (ppm) = 14.4 (C-18), 23.6 (C-17), 23.7-35.1 (C-11 to C-16, C2 to C-8), 60.9 (C-7 *), 64.7 (C-6 '), 71.7 (04), 74.9 (C-2'), 75.3 (C-5 '), 77.8 (C-3 '), 103.6 (C-1'), 117.1 (C-6 *), 123.1 (C-4 *), 129.0-132.8 (C-9, C-10, C-2 *, C- 3 *, C-5 *), 156.2 (C-1 *), 175.5 (C '= O).

Example 6 6-O-palmitoyl - ([2- (hydroxymethyl) phenyl] -β-D-glucopyranoside

5 mmol of D - (-) - salicin [2- (hydroxymethyl) phenyl-β-D-glucopyranoside] and 5 mmol of methyl palmitate in 50 ml of acetone were placed in a 2-neck flask with a Soxhlet extractor (which was filled with activated molecular sieve) 0.5 mg of immobilized Candida antartica B lipase (SP 435, manufacturer Novo Nordisk) were added and the mixture was heated to 40 ° C. for 48 hours with stirring (magnetic stirrer, 200 rpm) and reduced pressure. The progress of the reaction was monitored graphically using thin layer chromatography. After the end of the reaction, 14 g of warm (about 50 ° C.) acetone were added and the mixture was filtered at 50 ° C. The filtrate was cooled to -10 ° C and the resulting product was isolated by filtration in a yield of 53%.
¹³ C NMR (CD ₃ OD): δ (ppm) = 14.47 (C-16), 23.74 (C-15), 26.00 (C-3), 30.22-30.80 ( C-4-C-13), 33.08 (C-14), 35.03 (C-2), 60.98 (C-7 *), 64.59 (C-6 '), 71.64 (C-4 '), 74.96 (C-2'), 75.49 (C-5 '), 77.82 (C-3'), 103.22 (C-1 '), 117.07 (C-6 *), 123.82 (C.4 *), 129.78-132.34 (C-2 *, C-3 *, C-5 *), 156.98 (C-1 *) , 175.23 (C = O). Anal. Calculated for C ₂₉ H ₄₈ O ₈ (524.69): C, 66.39; H, 9.22. Found: C, 67.88; H, 9.41.

Examples 7 to 9 Production of further salicin esters by transesterification

In analogy to the process described in Example 6, salicin ([2- (hydroxymethyl) phenyl] -β-D-glucopyranoside) was reacted with various methyl carboxylates and the salicines esterified in the table below were selectively esterified to the primary alcohol function of the glucose unit .

The salicin esters thus prepared were characterized by NMR spectroscopy; the spectrum of example 9 is given by way of example:  

(Example 9) 6-O-phenylacetyl - ([2- (hydroxymethyl) phenyl] -β-D-glucopyranoside ¹³

C-NMR (CD ₃

OD): δ (ppm) = 41.82 (C-2), 60.99 (C-7 *), 65.03 (C-6 '), 71.52 (C-4'), 74.94 (C-2 '), 75.49 (C-5'), 77.77 (C-3 '), 103.21 (C-1'), 117.11 (C-6 *), 123.91 (C-4 *), 127.89 (C-6), 129.46 = 132.37 (C-2 *, C-3 *, C-5 *; C-4, C-5, C-7 , C-8), 136.12 (C-3), 156.95 (C-1 *), 173.31 (C = O). Anal. calculated for C21H ₂₄

O ₈

(404.41): C, 62.38; H, 5.98. found: C, 63.96; H, 5.90.

Example 10 Cytotoxicity (in mouse or human skin keratinocytes, MSCP 5 or HPK II)

The toxicity of the substances present was assessed using the MTT test (Mosmann 1983) in cell cultures. This test is based on the conversion of the yellow tetrazolium salt MTT in the violet dye formazan. The reaction only found in living cells through those in the inner mitochondrial membrane localized succinate dehydrogenase instead. Because of the possible use in Cosmetic or pharmaceutical products were skin cells (human HPKII or Mouse MSCP5 keratinocytes) was used as the test system. The substances tested (Phenylpropionyl salicin and p-OH-phenylacetyl salicin) were in Concentrations at which they showed biological activity (inhibition of Prostaglandin synthesis), not toxic to the cells. The effect of the substances on the keratinocyte was independent of the time (1.5 or 20 h incubation time), the state of growth (confluent or subconfluent) and the organism (Mouse or human).

Fig. 1 shows that the influence of phenylpropionyl-salicin (lower, solid curve) and p-OH-phenylacetyl-salicin (upper, dotted curve) on the vitality of skin cells (keratinocytes) was very small. The substances were dissolved in the culture medium and incubated with the cells for 20 h. The MTT reduction test was then carried out with fresh medium without test components.

Example 11 Inhibition of prostaglandin synthesis by salicin derivatives (in mouse or human skin keratinocytes, MSCP 5 or HPK II)

Fig. 2 shows the inhibitory effects of salicin and salicine esters on prostaglandin release in keratinocytes. The cells were labeled with 0.2 μCi ¹⁴ C-arachidonic acid ml ^-1 medium for 16 hours. The test substances were added in fresh medium with increasing concentration and incubated for 2 hours. In the figure, the substances mean:
1 = negative control,
2 = salicin,
3 = phenylpropionyl salicin,
4 = p-OH-phenylacetyl-salicin,
5 = positive control

In the positive control NS398 (10 µM) with MSCPS cells the Prostaglandin synthesis reduced by 85%. The prostaglandins were in the Compared to reference substances identified and radiodensitiometric quantified The average of three measuring points is given. MSCP 5: 100% = 201 cpm; HPK II: 100% = 63 cpm.

Example 12 Influencing the transcription activity of HPK II (human skin Keratinocytes)

Prostaglandin release can be at several levels by inhibitors to be influenced. In addition to inhibiting the catalytic activity of the Prostaglandin synthase proteins are already an effect on messenger RNA Cyclooxygenases conceivable. Northem blot analyzes showed that at Incubation of subconfluent MSCP 5 cells with 500 µM p-OH-phenylacetoyl Salicin for 45 minutes compared the COX-2 mRNA steady state concentration to untreated cells is greatly reduced. As a negative control, identical applied RNA concentration the cells in medium without Test substance only with the solubilizer acetone (0.25% v / v) for 45 minutes incubated.

Claims (11)

1. Salicyl alcohol derivatives of the general formula (I)
R ¹ -OCH ₂ -Ph-OZ- (R ² ) _n (I),
wherein
R ^{1 represents} a hydrogen atom or a radical C (O) R ³ ,
wherein R ^{3 is} an alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, or aryl radical having 1 to 26 carbon atoms and / or 1-10 heteroatoms, which is unbranched or branched, mono- or polyunsaturated and / or substituents on the carbon skeleton and / or can carry the heteroatoms means
Ph represents the 1,2-phenylene radical,
Z represents a sugar which is semi-acetally bound to the aromatic radical Ph in (I) and is substituted n-times with R ^{2 in an} ester-like manner, where the sugar can be a mono-, di-, oligo- or polysaccharide,
n is an integer between 0 and m, m being the number of free hydroxyl groups present in the semiacetal bond to the aromatic radical Z,
R ^{2 represents} a hydrogen atom or a group C (O) R ⁴ , where R ^{4 is selected} from the same group as R ³ , and where R ¹ and R ^{2 may be the} same or different with the proviso that at most one of the two R ¹ or R ^{2 are} hydrogen when Z = glucose,
and with the limitations
that when Z is glucose and R ^{2 are} hydrogen, the radical R ^{1 can} not be acetyl, benzoyl or (1-hydroxy-6-oxo-2-cyclohexen-1-yl) carbonyl,
and in the event that R ^{1 is} hydrogen, Z is glucose and n = 1 and the glucose radical on its primary hydroxyl group is substituted by R ² , the radical R ² cannot be 4-phenyl-butyryl. 2. salicyl alcohol derivatives according to claim 1, characterized in that at least one of the two radicals R ¹ and R ^{2 is} a hydrogen atom, the benzoyl, phenylacetyl, phenylpropionyl, phenylbutyryl, phenylvaleroyl, o-, m- or p-hydroxy -benzoyl-, o-, m- or p-hydroxy-phenylacetyl-, o-, m- or p-hydroxy-phenylpropionyl-, o-, m- or p-hydroxy-phenylbutyryl-, o-, m- or p -Hydroxy-phenylvaleroyl-, 3,4,5-trihydroxybenzoyl-, 3-phenylacryloyl, o-, m- or p-hydroxy-3-phenylacryloyl or 3- (3,4-dihydroxyphenyl) acryloyl group. 3. salicyl alcohol derivatives according to at least one of claims 1 and / or 2, characterized in that n = 1 and R ^{1 is} hydrogen. 4. salicyl alcohol derivatives according to at least one of claims 1 to 3, characterized in that Z is a monosaccharide selected from Threose, erythrose, arabinose, lyxose, ribose, xylose, allose, old rose, Galactose, glucose, gulose, idose, mannose, talose and fructose, being the naturally occurring stereoisomers of sugar are preferred. 5. salicyl alcohol derivatives according to at least one of claims 1 to 4, characterized in that Z stands for D-glucose. 6. salicyl alcohol derivatives according to claim 1, characterized in that in the event that R ^{1 is} hydrogen, Z glucose and n = 1 and the glucose is substituted on its primary hydroxyl group with R ² = C (O) R ⁴ , R ⁴ COOH means no hydrophobic aromatic carboxylic acid. 7. Process for the preparation of the compounds according to at least one of the Claims 1 to 6, characterized in that an alcoholic Component with a carboxylic acid, a carboxylic acid ester or activated carboxylic acid derivative in the presence of suitable catalysts is esterified or transesterified. 8. The method according to claim 7, characterized in that the production is carried out by an enzymatically catalyzed esterification or transesterification.   9. Use of the compounds according to at least one of claims 1 to 6 for the production of cosmetic and / or pharmaceutical Preparations. 10. Cosmetic preparations, characterized in that they Salicyl alcohol derivatives according to at least one of Claims 1 to 6 contain. 11. Pharmaceutical preparations, characterized in that they Salicyl alcohol derivatives according to at least one of Claims 1 to 6 contain.